Imbalances in membrane excitability underlie a broad range of cardiac arrhythmias and conduction defects. Although we now know the genes encoding almost all ion channels, we have little understanding of how the macromolecular composition and relative numbers of different channel types is achieved to exert exquisite control over membrane potential changes in time. Even minor changes in this balance can lead to sudden
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The mechanisms involved reside at every conceivable level – genomic and epigenetic, transcriptional, translational and posttranslational. The tools required include structural biology, super resolution microscopy, single-molecule measurements, advanced molecular biology approaches, and bioinformatics and systems biology approaches. Fulfilling this unmet need will inform any system in which stoichiometry of macromolecular complexes critically determines normal function, and will therefore have a broad, transformative reach. The work will reveal novel mechanisms that will serve as targets for disease and therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC:

Addressing this problem requires coordinated efforts by multidisciplinary investigators using diverse approaches as described above. Above all it requires a commitment of resources to basic science advances without which translation is impossible.

Name of idea submitter and other team members who worked on this idea:
Gail Robertson

Voting

There is an urgent need to understand the mechanisms underlying diabetes-induced congenital heart defects (CHDs) through basic science research and biomarker identification in human maternal circulation. Majority of the current research in CHDs is related to genetic analyses; however, environmental factors contribute to the majority of human CHDs, but the underlying mechanism is unknown. There is 60 million worldwide
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More than 32,000 infants are born with heart defects each year in the United States, and about 1 in 150 adults are expected to have some form of congenital heart defect. Approximately, 25% of infants born with heart defects (2.4 per 1,000 live births) require invasive treatment in the first year of life, and in 2009 heart defects were the most common cause of infant death. Therefore, understanding the underlying causes of abnormal heart formation is an essential step towards developing effective new therapeutic treatments or preventions for heart defects. Using diabetes-induced CHDs as research models will reveal critical molecular pathways that contributes to heart cell proliferation and apoptosis.

Feasibility and challenges of addressing this CQ or CC:

The same types of heart defects seen in human diabetic pregnancies can be recapitulated in diabetic animal models, making rodents ideal models to investigate how maternal hyperglycemia may induce congenital heart defects. Dietary supplements of natural compounds may be effective against CHDs in diabetic pregnancies. Clinically, new imaging techniques needs be developed for the early diagnosis of CHDs in diabetic pregnancies. Biomarkers in human blood samples needs be detailed analyzed so that we can use small molecules such as microRNA for reliable and early diagnosis.

Name of idea submitter and other team members who worked on this idea:
Peixin Yang

Voting

Here's an article on the "Mincome" program which Canada tested in the 1970's in a small town:
http://www.dominionpaper.ca/articles/4100
It had many positive effects on people's lives and health.
Quotes:
'In the period that Mincome was administered, hospital visits dropped 8.5 per cent.'
[...]
'“When you walk around a hospital, it's pretty clear that a lot of the time what we're treating are the consequences of poverty,”
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Voting

1) Refinement of COPD subphenotypes for therapeutics, diagnostics and mechanistic interrogation. The NIH should encourage a strong focus on a) rigorous, mechanistically-reinforced definitions (chronic bronchitis, emphysema (with and without obstruction), frequent exacerbators, combined pulmonary fibrosis and emphysema) and 2) the development and optimization of animal model systems that replicate the different subphenotypes.
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If we could develop less costly and time consuming cell and animal models of COPD that reflect meaningful subphenotypes, we would be able to not only probe basic mechanism but also have reliable test platforms for candidate therapies.

There is typically a major obstacle between the acquisition of big data from observational disease cohorts, often broad but superficial, and the translation of these findings to basic discovery efforts. The clinical researchers speak a different language than the basic investigators and traversing this chasm with grant enticements might prove helpful.

Feasibility and challenges of addressing this CQ or CC:

This would require some suspension of the classic mechanistic, hypothesis driven proposals to develop these research tools.

There would need to be some reconstruction of study sections to permit these combined clinical-basic grants. The translational PPG was in keeping with this but should be reinforced with smaller grant programs such as RO1 level grants.

Name of idea submitter and other team members who worked on this idea:
lungmatbio1

Voting

We need much more support for critical basic research to understand and develop transformative therapies for this enormous health care burden. This is not simply a question of epidemiology and large multicenter population data bases. We really need hard core science. It is impossible to know where the next breakthrough will come, and setting aside funds for hot button things - stem cells, or iPS, or gene editing per
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NIH needs to stop trying to guess what the next big thing is and putting funds aside to support something that is popular at the moment. This has been done frankly with GWAS, with Stem cells, and perhaps ongoing now with "personalized medicine". All hot areas, but so are a ton of other things. IN my 30 years as a physician scientist, I cannot count on one hand the number of discoveries that were really transformative that came out of this type of ear-marked planning. Need more resources to support innovative individual scientists, particularly those with a track record of discovery, translation, and iinnovation We do not do that well enough at all.

Voting

Basic scientists and clinicians have different training and bring different perspectives to lung disease research. Additionally, mechanisms that facilitate interactions of scientists from different fields may improve communication and facilitate novel ideas for lung disease research. I would like to see a funding mechanism that encouraged such partnerships in addressing fundamental disease questions and/or treatments.
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This mechanisms could bring more perspectives to bear on questions in lung disease and would facilitate multi-disciplinary interactions and ideas.

Feasibility and challenges of addressing this CQ or CC:

If single awards, budgets would need to be large enough to allow for funding basic science as well as providing dollars to collect clinical samples. It should be possible to support some core facility infrastructure if needed and allow a budget that could account for basic scientists, animal work, study coordinators, clinicians, etc. Perhaps the RFA could require at least 3 different fields to be represented to try to facilitate multi-disciplinary approaches. Such a mechanism could help replace the loss of grants like SCOR grants and PPGs.

Name of idea submitter and other team members who worked on this idea:
Beth Moore

Voting

So much basic cardiovascular discovery relies on cell culture models. While cardiac cell lines exist (e.g. HL-1, H9c2), these often poorly model aspects of cardiomyocyte function in-situ (e.g. contractile function, metabolism). In contrast, primary cardiomyocytes isolated from adult animals (especially mice!) are not readily amenable to culture conditions. Even if cells can be kept alive, they are often refractory to
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Addressing this challenge would provide tools for basic researchers to answer many key questions about basic cardiomyocyte function. Removing the "voodoo" element from these methodologies would be an enabling technology. In the neuron field, companies such as "brain bits" will ship tissue with specific protocols, to enable unskilled technicians to culture highly pure neuron subtypes in a matter of hours. Such methods have led to standardized methods in the field, which is good for reproducibility.

Feasibility and challenges of addressing this CQ or CC:

There have been several attempts at keeping adult myocytes alive in culture, using technologies such as electrical pacing, and inclusion of inhibitors in culture media. Likewise some AAV variants are known to transfect hearts in-vivo. However, no uniform widely-accepted methods are used between many different labs. Every lab has their own "trick" to get cells to behave. Many investigators can make a few cells on a dish survive, which is sufficient for single cell work (e.g. microscopy), but getting an entire culture of adult myocytes to survive beyond 24-48 hrs (the minimal time frame needed for genetic manipulations such as siRNA) would open up more common detection and assay measurements. Myocytes from larger animals (e.g. rabbits) are more stable and longer-lived in culture, but such methods do not appear to work for mouse CMs, which therefore precludes application of knockouts and other useful mouse resources.

Name of idea submitter and other team members who worked on this idea:
Paul Brookes

Voting

Unless we fix and increase the R01 funding rate, which most basic scientists depend upon, we will continue to lose outstanding scientists of all ages and not have the next generation of scientists or the numbers of currently outstanding scientists to answer any of these compelling questions and critical challenges. Related to this, much has been written about the significant failure rate of clinical trials in part due
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Voting

What HIV/AIDS-related basic research can NHLBI support in the next 5-10 years to investigate the fundamental mechanisms of HIV-related heart, lung, and/or blood (HLB) diseases alone and in the context of antiretroviral therapy (ART) to improve heart, lung, and blood health outcomes in HIV infections as well as the fundamental mechanisms of hematopoietic stem cell transplantation in potential elimination or eradication
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Widespread availability of effective antiretroviral therapy (ART) has changed the epidemiology of AIDS. HIV-infected patients on ART can expect to live for many decades, but now chronic diseases are increasingly replacing acute infections as important causes of morbidity and death. A growing body of evidence suggests that HIV may alter and/or accelerate the natural history of fundamental processes underlying atherosclerosis, pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), pulmonary co-infections, anemia, coagulation, thrombotic disorders, and immune senescence.

However, the mechanisms by which HIV and ART may modify these processes have not been fully elucidated, primarily because of the multiple direct and indirect pathways by which HIV and ART induce cellular dysfunction. Advancing knowledge of which cell types are affected by HIV (and serve as reservoirs), as well as increased understanding of the vital interactions between HIV and the host cells as well as interactions between HIV and other elements of the human virome and the broader microbiome is essential to elucidating the pathogenesis of HIV-related HLB diseases.

The use of basic research models will complement and extend the results of clinical studies.

Feasibility and challenges of addressing this CQ or CC:

For HIV infection and heart, lung, and blood health and diseases:

• NHLBI investments in this aspect, including the three RFAs in 2014-2015, two on basic research and one on clinical research, have laid good foundation.

• Collaborations between HIV investigators and HLB investigators that have been facilitated by the NHLBI investments including the three RFAs.

• The Berlin patient has provided the proof of concept that HIV infection can be eradicated, that is, sterilizing cure can be achieved, through HSC transplantation in combination with other therapies.

• New technologies that have been developed recently, such as the deep sequencing techniques and research supported by the NIH Human Microbiome Program and other programs have allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the human virome.

Voting

What is necessary to reprogram the immune system to improve transplant outcomes of hearts, lungs, and hematopoietic cells?
While NIAID is a major funder of immunology research, we are a major contributor to stem cell research. Our resources could be combined, where NIAID would support this approach for autoimmune diseases, and we would support work in tolerance for transplants.
If the NCI also wants to collaborate on
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This innovative and transformative proposal could improve tolerance to many different types of transplants.

Feasibility and challenges of addressing this CQ or CC:

In 2002, Hochedlinger and Jaenisch (Nature 415:1035-1038) created a mouse by nuclear transplantation from a mature B-cell. This was proof of principle that the immune system can be reprogrammed entirely. Since then there has been little work in this area, but Reprogramming Immune System Cells (RISC) is risky but promising.

A second approach involves mechanisms that cancer cells use to evade immune detection. While most cancer research works to restore immune competence for therapy, the basic biology of evading immune detection could be exploited to improve tolerance. These approaches could be tested in an animal model in 5 years.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

Could lead to the development of fundamental knowledge required to develop effective new therapeutic interventions to treat heart disease.

Feasibility and challenges of addressing this CQ or CC:

Several studies have already demonstrated associations been NANC transmitter release and neuropeptide co-localization with pathogenic changes in cardiac function.

Identification within cardiac nerves of neural peptides that are co-released with traditional transmitters is an interesting and still emerging story. Studies with nonadrenergic, noncholinergic (NANC) transmitters in both the atria and ventricle have shown that a variety of neuropeptides also are localized within the heart, and several, including vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P, and calcitonin gene-related peptide, have been shown to markedly affect heart rate and modulate cardiac function. NPY is also elevated in heart failure patients, and other neuropeptides, including VIP, calcitonin gene related peptide (CGRP), substance P (SP) and their receptors are associated with various types of cardiomyopathies.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.